Publications by authors named "Lothar Bergmann"

45 Publications

Real-world outcomes in patients with metastatic renal cell carcinoma according to risk factors: the STAR-TOR registry.

Future Oncol 2021 Mar 16. Epub 2021 Mar 16.

University Hospital Muenster, 48149 Muenster, Germany.

Examine outcomes in sunitinib-treated patients by International Metastatic RCC Database Consortium (IMDC) or Memorial Sloan-Kettering Cancer Center (MSKCC) risk factors. Patients enrolled in STAR-TOR registry (n = 327). End points included overall survival, progression-free survival and objective response rate. Overall survival was similar for IMDC 0 versus 1 (p = 0.238) or 2 versus ≥3 (p = 0.156), but different for MSKCC (0 vs 1, p = 0.037; 2 vs ≥3, p = 0.001). Progression-free survival was similar for IMDC 2 versus 3 (p = 0.306), but different for MSKCC (p = 0.009). Objective response rate was different for IMDC 1 (41.9%) and 2 (29.5%) and similar for MSKCC 1 (34.4%) and 2 (31.0%). Outcome data varied according to IMDC or MSKCC. MSKCC model accurately stratify patients into risk groups. Clinical trial registration: NCT00700258 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-1020DOI Listing
March 2021

[Interdisciplinary recommendations for the treatment of advanced metastatic renal cell carcinoma].

Aktuelle Urol 2020 Dec 7;51(6):572-581. Epub 2020 Oct 7.

Medizinische Hochschule Hannover, Urology, Hannover.

Due to novel therapies, the prognosis of patients with metastatic renal cell carcinoma (mRCC) has improved. A median overall survival of more than two years is a realistic goal. Immunotherapy combinations with checkpoint inhibitors or checkpoint inhibitors and the tyrosine kinase inhibitor axitinib are new first-line options.Sunitinib, pazopanib, tivozanib and the combination of bevacizumab + interferon alpha are approved for first-line therapy regardless of the progression risk score. The use of both the combination of nivolumab + ipilimumab and cabozantinib is restricted to intermediate and high-risk patients. In this subgroup, the immunotherapy combination was more effective in terms of overall survival compared with sunitinib. Temsirolimus is only approved for high-risk patients.Sunitinib and pazopanib can also be applied as second-line options - for pazopanib the use is restricted to the event of cytokine failure. Nivolumab and cabozantinib demonstrated superior overall survival compared with everolimus. Furthermore, the combination of lenvatinib + everolimus and axitinib are approved treatment options in the second-line and further settings. Everolimus has been replaced in the second-line setting by these new options.The question regarding the optimal sequence is still unanswered.The purpose of an interdisciplinary expert meeting was to debate which criteria should influence treatment. The members discussed several aspects of treating patients with advanced or metastatic RCC. As in previous years, the experts intended to provide recommendations for clinical practice. The results are presented in this publication.
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http://dx.doi.org/10.1055/a-1252-1780DOI Listing
December 2020

Effect of comorbidities/comedications on sunitinib outcomes for metastatic renal cell carcinoma: the STAR-TOR registry.

Future Oncol 2020 Dec 6;16(35):2939-2948. Epub 2020 Oct 6.

Klinik für Urologie, Universitätsmedizin Göttingen, Göttingen, Germany.

Examine the effects of baseline hypertension (HTN) and statin or proton pump inhibitor (PPI) use on sunitinib treatment outcomes in STAR-TOR, a real-world registry. Presence or absence of HTN and use or nonuse of statins or PPIs were determined at registry entry. End points included overall survival (OS) and progression-free survival (PFS). Data were from 557 patients. Presence or absence of HTN did not affect OS or PFS. PFS (median [95% CI]) was longer in statin users (9.4 [6.5-13.6] months) versus nonusers (6.9 [5.7-8.2] months) (p = 0.0442). OS was shorter in PPI users (20.2 [14.9-28.3] months) versus nonusers (25.7 [22.7-33.0] months) (p = 0.0212). Comorbidities and comedications may affect real-world sunitinib treatment outcomes. Clinical Trial Registration: NCT00700258 (ClinicalTrials.gov).
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http://dx.doi.org/10.2217/fon-2020-0548DOI Listing
December 2020

Consensus paper: current state of first- and second-line therapy in advanced clear-cell renal cell carcinoma.

Future Oncol 2020 Oct 23;16(29):2307-2328. Epub 2020 Sep 23.

Interdisciplinary GU Oncology, Clinic for Medical Oncology & Clinic for Urology, University Hospital Essen, D-45147, Essen, Germany.

The therapy of advanced (clear-cell) renal cell carcinoma (RCC) has recently experienced tremendous changes. Several new treatments have been developed, with PD-1 immune-checkpoint inhibition being the backbone of therapy. Diverse immunotherapy combinations change current first-line standards. These changes also require new approaches in subsequent lines of therapy. In an expert panel, we discussed the new treatment options and how they change clinical practice. While first-line immunotherapies introduce a new level of response rates, data on second-line therapies remains poor. This scenario poses a challenge for clinicians as guideline recommendations are based on historical patient cohorts and agents may lack the appropriate label for their in guidelines recommended use. Here, we summarize relevant clinical data and consider appropriate treatment strategies.
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http://dx.doi.org/10.2217/fon-2020-0403DOI Listing
October 2020

A Randomized Phase IIa Trial with Temsirolimus versus Sunitinib in Advanced Non-Clear Cell Renal Cell Carcinoma: An Intergroup Study of the CESAR Central European Society for Anticancer Drug Research-EWIV and the Interdisciplinary Working Group on Renal Cell Cancer (IAGN) of the German Cancer Society.

Oncol Res Treat 2020 15;43(7-8):333-339. Epub 2020 Jun 15.

Department of Medical Oncology, West German Cancer Center, University Hospital Essen of the University Duisburg-Essen, Essen, Germany.

Background: Non-clear cell renal cell cancers (nccRCC) are rare entities, and the optimal therapy in metastatic disease has still to be defined.

Methods: In this small prospectively randomized phase IIa multicenter trial, we investigated temsirolimus (TEM) versus sunitinib (SUN) as first-line therapy in patients with metastatic nccRCC. The patients were randomized 1:1 to either TEM in a dose of 25 mg i.v. once a week or SUN with 50 mg p.o. daily for 4 weeks on and 2 weeks off. Primary endpoint was progression-free survival (PFS). In total, 22 patients were included with predominantly papillary RCC (16/22) followed by chromophobe RCC and others.

Results: The male to female ratio was 16:6. The tumor control rate (CR + PR + SD) was 58% for TEM and 90% for SUN-treated patients. There was also a trend for improved PFS with 9.3 versus 13.2 months (HR 1.64; 95% CI 0.65-4.18) in favor of SUN. There was no trend for overall survival.

Conclusions: Despite this trial had to be terminated earlier due to low recruitment, the results match the other studies published so far with the mTOR inhibitor everolimus and SUN, which show a trend in favor of SUN for ORR and PFS.
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http://dx.doi.org/10.1159/000508450DOI Listing
September 2020

[What is new in the diagnosis and therapy of renal cell carcinoma?]

Dtsch Med Wochenschr 2020 06 3;145(11):734-739. Epub 2020 Jun 3.

Medizinische Klinik 2, Hämatologie und Onkologie, Universitätsklinikum der Johann-Wolfgang-Goethe-Universität Frankfurt, Frankfurt am Main.

Renal cell carcinomas (RCC) include different tumor entities, of which clear cell RCC is the most common tumor with approx. 75 % followed by the papillary RCC with 10-15 %. RCC are increasingly being diagnosed incidental in the context of abdominal diagnostics from other indications using sonography or cross-sectional imaging.The prognosis of metastatic RCC has improved significantly due to new therapy options, especially through the use of immune checkpoint inhibitors (IO). In the first line, combination therapies of the tyrosine kinase inhibitor (TKI) axitinib with the PD-1 antibody pembrolizumab or the PDL-1 antibody avelumab apply regardless of the risk profile and histological entity, as well as the combination of the CTLA4 antibody ipilimumab with the PD-1 antibody nivolumab in patients with intermediate and high risk as new standards in therapy. The combinations lead to a higher response rate and longer survival. In the second line and subsequent lines, there is no evidence-based data after combination therapies, but drugs can be used that were not yet part of the first-line therapy.
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http://dx.doi.org/10.1055/a-0982-4331DOI Listing
June 2020

Outcomes based on age in the phase III METEOR trial of cabozantinib versus everolimus in patients with advanced renal cell carcinoma.

Eur J Cancer 2020 02 27;126:1-10. Epub 2019 Dec 27.

Dana-Farber Cancer Institute, Boston, MA, USA.

Background: Cabozantinib improved progression-free survival (PFS), overall survival (OS) and objective response rate (ORR) compared with everolimus in patients with advanced renal cell carcinoma (RCC) after prior antiangiogenic therapy in the phase III METEOR trial (NCT01865747). Limited data are available on the use of targeted therapies in older patients with advanced RCC.

Methods: Efficacy and safety in METEOR were retrospectively analysed for three age subgroups: <65 (n = 394), 65-74 (n = 201) and ≥75 years (n = 63).

Results: PFS, OS and ORR were improved with cabozantinib compared with everolimus in all age subgroups. The PFS hazard ratios (HRs) were 0.53 (95% confidence interval [CI]: 0.41-0.68), 0.53 (95% CI: 0.37-0.77) and 0.38 (95% CI: 0.18-0.79) for <65, 65-74 and ≥75 years, respectively, and the OS HRs were 0.72 (95% CI: 0.54-0.95), 0.66 (95% CI: 0.44-0.99) and 0.57 (95% CI: 0.28-1.14). The ORR for cabozantinib versus everolimus was 15% vs 5%, 21% vs 2% and 19% vs 0%, respectively. No significant differences were observed in PFS or OS with age as a categorical or continuous variable. Grade III/IV adverse events (AEs) were generally consistent across subgroups, although fatigue, hypertension and hyponatraemia occurred more frequently in older patients treated with cabozantinib. Dose reductions to manage AEs were more frequent in patients receiving cabozantinib than in those receiving everolimus. Dose reductions and treatment discontinuation due to AEs were more frequent in older patients in both treatment groups.

Conclusions: Cabozantinib improved PFS, OS and ORR compared with everolimus in previously treated patients with advanced RCC, irrespective of age group, supporting use in all age categories. Proactive dose modification and supportive care may help to mitigate AEs in older patients while maintaining efficacy.
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http://dx.doi.org/10.1016/j.ejca.2019.10.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521477PMC
February 2020

[Interdisciplinary recommendations for the treatment of metastatic renal cell carcinoma].

Aktuelle Urol 2019 Sep 4. Epub 2019 Sep 4.

Medizinische Hochschule Hannover, Klinik für Urologie und Urologische Onkologie, Hannover.

Due to novel therapies, the prognosis of patients with metastatic renal cell carcinoma has improved significantly. A median overall survival of more than two years is a realistic goal. Immunotherapies with checkpoint inhibitors are new first-line and second-line options. Sunitinib, Pazopanib, Tivozanib and the combination of Bevacizumab + interferon alpha are approved for first-line therapy, regardless of the progression risk score. The use of both the combination Nivolumab + Ipilimumab and Cabozantinib is limited to intermediate and high-risk patients. In this subgroup, the immunotherapy combination was more effective in terms of overall survival compared with Sunitinib. Temsirolimus is only approved for high-risk patients. Sunitinib and Pazopanib can also be used as second-line options, with the use of Pazopanib being limited to the event of cytokine failure. Nivolumab and Cabozantinib demonstrated superior overall survival compared to Everolimus. Furthermore, the combination of Lenvatinib + Everolimus and Axitinib are approved treatment options in second-line and further settings. Everolimus monotherapy has been replaced by the new options. The question regarding the optimal sequence of treatments is still unanswered. An interdisciplinary expert meeting aimed to discuss the criteria that should be used for therapy. The members discussed several aspects of treating patients with RCC. As in previous years, the experts intended to provide recommendations for clinical practice. The results are presented here.
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http://dx.doi.org/10.1055/a-0972-0914DOI Listing
September 2019

Non-Clear Cell Renal Cell Carcinoma - Pathology and Treatment Options.

Oncol Res Treat 2019 23;42(3):128-135. Epub 2019 Feb 23.

Non-clear cell renal cell carcinomas (nccRCC) are rare diseases with heterogeneous histopathologically and genetically defined entities. The clinical data on optimal systemic treatments of nccRCC is rather limited. In this review, the current World Health Organization (WHO) classification of nccRCC based on histopathologic and genetic findings is reported. Regarding systemic treatment options, the most commonly used agents are mTOR inhibitors like everolimus or temsirolimus, or tyrosine kinase inhibitors like sunitinib. 2 small randomized clinical trials with nccRCC comparing sunitinib with everolimus revealed a trend towards a better progression-free survival (PFS) and overall survival (OS) in favor of sunitinib. In RCC with predominant sarcomatoid features, both chemotherapy and targeted agents are reported without any preference for outcome. For subsequent lines of therapy, some case reports describe promising effects of PD-1 or PD-L1 inhibitors in nccRCC including sarcomatoid subtype and Bellini duct carcinoma. Currently, nccRCCs are treated similarly to clear cell RCC or, whenever possible, within clinical trials. Clinical trials with immune checkpoint inhibitors are ongoing.
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http://dx.doi.org/10.1159/000495366DOI Listing
August 2019

Final Results of a Non-Interventional Study Evaluating the Quality of Life in Second-line Treatment of Metastatic Renal Cell Carcinoma With Everolimus: The EVERPRO Study.

Oncol Res Treat 2019 19;42(1-2):57-66. Epub 2019 Jan 19.

Background: This study assessed the quality of life (QoL) and the implication of time effort of everolimus treatment in patients with metastatic renal cell carcinoma (mRCC).

Methods: Adult patients with mRCC were eligible for everolimus treatment after first-line vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors or bevacizumab therapy. The primary end-point, QoL, was assessed by means of the NCCN-FACT FKSI-19 questionnaire.

Results: In total, 202 patients (24% of female patients; median age, 71 years) were evaluable for QoL analyses. The median treatment duration was 4.4 months (95% CI, 3.8-5.3) and the median time to progression was 6 months (95% CI, 5.4-7.5). The median FKSI-19 total score remained stable during treatment (52.0 at therapy start, 55.0 at observation end). The median time effort spent on total therapy was 20 hours per patient. Most of the patients stated to have "no limitations," "a little" or "moderate" limitations in their daily, social, and professional lives. Two months after the start of treatment, 65 patients reported none or a little time burden due to therapy.

Conclusions: QoL was maintained during the everolimus therapy and limitations as well as time effort were acceptable for most of the patients. The study supports previous findings on switching mode of action after anti-VEGFR-targeted therapy to a mammalian target of rapamycin inhibitor.
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http://dx.doi.org/10.1159/000494278DOI Listing
August 2019

[Interdisciplinary Recommendations for the Treatment of Metastatic Renal Cell Carcinoma].

Aktuelle Urol 2017 Feb 12;48(1):72-78. Epub 2017 Apr 12.

Charité-Med. Klinik III und Charité Comprehensive Cancer Center.

Thanks to the use of targeted therapies, the prognosis of patients with metastatic renal cell carcinoma (mRCC) has improved significantly. A median overall survival of more than 2 years is a realistic claim. These improvements are also reflected in recent discussions about 3 and more lines of therapy.Sunitinib, pazopanib, the combination of bevacizumab and interferon alpha, and temsirolimus are approved for first-line therapy of mRCC. Sunitinib and pazopanib are also approved for second-line therapy, which, for pazopanib, is confined to the use after cytokine failure. Everolimus (after tyrosine kinase inhibitor (TKI) treatment), sorafenib (after cytokines) and axitinib (after treatment with sunitinib or cytokines) are other compounds available for second-line therapy.3 new substances have recently been approved for second-line therapy: Nivolumab, cabozantinib, and lenvatinib combined with everolimus can be used after VEGF-targeted treatment has failed. It is for the first time that targeted immunotherapy and a combination of targeted substances are available for the treatment of mRCC.There is no new insight as to an optimal sequence therapy. Study results from a phase III trial suggest that the sequences sorafenib-sunitinib and sunitinib-sorafenib are equally effective.The purpose of an interdisciplinary expert meeting on RCC was to work out joint treatment recommendations based on current data and clinical experience and to integrate them into clinical routine practice. The results are presented in this publication.
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http://dx.doi.org/10.1055/s-0042-117572DOI Listing
February 2017

[Systemic therapy of metastatic renal cell carcinoma].

Dtsch Med Wochenschr 2016 Apr 31;141(7):466-9. Epub 2016 Mar 31.

In metastatic ccRCC , the treatment options in 1st line treatment are still the tyrosinkinase inhibitors (TKI) pazopanib and sunitinib, for patients with low or intermediate risk additionally IFNα/bevacizumab and for high risk patients the mTOR inhibitor temsirolimus. In 2nd line following cytokine therapy, axitinib or pazopanib and following TKI /VEGF directed therapy axitinib or everolimus may be administered. New upcoming agents in RCC are the PD1 antibody nivolumab and the multikinase inhibitor Cabozantinib, which both showed an OS advantage compared to everolimus. After marketing authorization in Europe, these agents should therefore be preferred in 2nd and 3rd line therapy. Further agents are under investigation.
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http://dx.doi.org/10.1055/s-0042-104594DOI Listing
April 2016

The European Medicines Agency Review of Brentuximab Vedotin (Adcetris) for the Treatment of Adult Patients With Relapsed or Refractory CD30+ Hodgkin Lymphoma or Systemic Anaplastic Large Cell Lymphoma: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use.

Oncologist 2016 Jan 30;21(1):102-9. Epub 2015 Nov 30.

European Medicines Agency, London, United Kingdom.

Background: On October 25, 2012, a conditional marketing authorization valid throughout the European Union (EU) was issued for brentuximab vedotin for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma (HL) and for the treatment of adult patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). For HL, the indication is restricted to treatment after autologous stem cell transplantation (ASCT) or after at least two previous therapies when ASCT or multiagent chemotherapy is not a treatment option.

Materials And Methods: Brentuximab vedotin is an antibody-drug conjugate (ADC) composed of a CD30-directed monoclonal antibody (recombinant chimeric IgG1) that is covalently linked to the antimicrotubule agent monomethyl auristatin E (MMAE). Binding of the ADC to CD30 on the cell surface initiates internalization of the MMAE-CD30 complex, followed by proteolytic cleavage that releases MMAE. The recommended dose is 1.8 mg/kg administered as an intravenous infusion over 30 minutes every 3 weeks.

Results: Brentuximab vedotin as a single agent was evaluated in two single-arm studies. Study SG035-003 included 102 patients with relapsed or refractory HL. An objective response was observed in 76 patients (75%), with complete remission in 34 (33%). Study SG035-004 included 58 patients with relapsed or refractory sALCL. An objective response was observed in 50 patients (86%), with complete remission in 34 (59%). The most frequently observed toxicities were peripheral sensory neuropathy, fatigue, nausea, diarrhea, neutropenia, vomiting, pyrexia, and upper respiratory tract infection.

Conclusion: The present report summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of the product characteristics, are available on the European Medicines Agency website (http://www.ema.europa.eu).

Implications For Practice: Brentuximab vedotin was approved in the European Union for the treatment of adult patients with relapsed or refractory CD30+ Hodgkin lymphoma or systemic anaplastic large cell lymphoma. For Hodgkin lymphoma, brentuximab vedotin should only be used after autologous stem cell transplantation or following at least two prior therapies when transplantation or multiagent chemotherapy is not a treatment option. In two studies involving 160 patients, partial or complete responses were observed in the majority of patients. Although there was no information on the survival of patients treated in the studies at the time of approval, the responses were considered a clinically relevant benefit.
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http://dx.doi.org/10.1634/theoncologist.2015-0276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709212PMC
January 2016

Everolimus for patients with metastatic renal cell carcinoma refractory to anti-VEGF therapy: results of a pooled analysis of non-interventional studies.

Eur J Cancer 2015 Nov 11;51(16):2368-74. Epub 2015 Aug 11.

University Hospital Frankfurt, Tumor Center Rhein-Main, Frankfurt/Main, Germany.

Aim: To assess the efficacy and safety of everolimus in patients with metastatic renal cell carcinoma (mRCC) who failed one or two anti-VEGF therapies.

Patients And Methods: Data from four prospective, non-interventional studies conducted in Germany, France, Greece and Austria were pooled for this analysis. Patients with mRCC of any histology (clear cell or non-clear cell) were included. VEGF-refractory patients received everolimus 10mg/day until disease progression or unacceptable toxicity. The primary objective was to determine everolimus efficacy as measured by time to progression (TTP; from baseline to progression).

Results: The overall population comprised 632 patients; 493 patients received everolimus in the second-line setting. Most patients were of favourable/intermediate MSKCC risk (91%), had clear cell mRCC (89%), and had undergone nephrectomy (89%). Median TTP was 6.3months (95% confidence interval [CI], 5.9-6.8) for the overall population and 6.4months (95% CI, 5.8-6.9) for the second-line everolimus population. Similarly, median progression-free survival was 5.5months (95% CI, 5.0-6.1) for the overall population and 5.8months (95% CI, 5.0-6.4) for second-line everolimus population. Best tumour response (n=349) was complete or partial remission in 12% of patients and stable disease in 59% of patients. Overall population median overall survival (OS) was 11.2months (95% CI, 9.0-not reached). Commonly reported adverse events (AEs) (any grade) were stomatitis (25%), anaemia (15%) and asthenia (11%).

Conclusions: Results of this pooled analysis provide evidence of safety and effectiveness of second-line everolimus in routine clinical use and support everolimus as a standard of care for VEGF-refractory patients with mRCC.
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http://dx.doi.org/10.1016/j.ejca.2015.07.030DOI Listing
November 2015

[What opportunities does Immuno-oncology indicate for overarching long-term survival?].

Oncol Res Treat 2015 28;38 Suppl 3:6-11. Epub 2015 Apr 28.

Medizinische Klinik II: Hämatologie/Onkologie, Universitätsklinikum Frankfurt, Frankfurt/M., Deutschland.

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http://dx.doi.org/10.1159/000381363DOI Listing
February 2016

Everolimus in metastatic renal cell carcinoma after failure of initial anti-VEGF therapy: final results of a noninterventional study.

BMC Cancer 2015 Apr 18;15:303. Epub 2015 Apr 18.

Department of Urology, University Hospital Munich-Grosshadern, Marchioninistrasse, 15, 81377, Germany.

Background: Data are limited regarding routine use of everolimus after initial vascular endothelial growth factor (VEGF)-targeted therapy. The aim of this prospective, noninterventional, observational study was to assess efficacy and safety of everolimus after initial VEGF-targeted treatment in patients with metastatic renal cell carcinoma (mRCC) in routine clinical settings.

Methods: Everolimus was administered per routine clinical practice. Patients with mRCC of any histology from 116 active sites in Germany were included. The main objective was to determine everolimus efficacy in time to progression (TTP). Progression-free survival (PFS), treatment duration, tumor response, adherence to everolimus regimen, treatment after everolimus, and safety were also assessed.

Results: In the total population (N = 334), median follow-up was 5.2 months (range, 0-32 months). Median treatment duration (safety population, n = 318) was 6.5 months (95% confidence interval [CI], 5-8 months). Median TTP and median PFS were similar in populations investigated. In patients who received everolimus as second-line treatment (n = 211), median (95% CI) TTP was 7.1 months (5-9 months) and median PFS was 6.9 months (5-9 months). Commonly reported adverse events (safety population, n = 318) were dyspnea (17%), anemia (15%), and fatigue (12%). Limitations of the noninterventional design should be considered.

Conclusions: This study reflects routine clinical use of everolimus in a large sample of patients with mRCC. Favorable efficacy and safety were seen for everolimus after previous therapy with one VEGF-targeted agent. Results of this study confirm everolimus as one of the standard options in second-line therapy for patients with mRCC. Novartis study code, CRAD001LD27: VFA registry for noninterventional studies ( http://www.vfa.de/de/forschung/nisdb/).
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http://dx.doi.org/10.1186/s12885-015-1309-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413536PMC
April 2015

Treatment algorithm for metastatic renal cell carcinoma--recommendations based on evidence and clinical practice.

Oncol Res Treat 2014 21;37(3):136-41. Epub 2014 Feb 21.

Medizinische Klinik II, Universitätsklinik Frankfurt, Frankfurt am Main, Germany.

Until a few years ago, the treatment options for metastatic renal cell cancer (mRCC) were very limited. The growing understanding of the molecular pathomechanisms underlying RCC allowed the development of new treatment approaches. Meanwhile, several approved target-oriented substances from different drug classes are available for mRCC. The mechanism of action of vascular endothelial growth factor (VEGF) and VEGF receptor or mTOR inhibition is well documented by phase III trials and reflected in the current guidelines. However, no predictive biomarkers have been identified in mRCC so far to demonstrate a benefit by a specific compound in an individual patient. Meanwhile, the sequential use of 'targeted therapies' in mRCC has been established as standard treatment. The optimal sequence of available agents is still unclear. A German RCC expert panel discussed and developed an algorithm for the choices of first- and second-line treatment in mRCC based on established clinical criteria.
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http://dx.doi.org/10.1159/000360179DOI Listing
December 2014

Therapy of mRCC beyond mTOR-inhibition in clinical practice: results of a retrospective analysis.

J Cancer Res Clin Oncol 2014 May 21;140(5):823-7. Epub 2014 Feb 21.

Department of Internal Medicine II, Hematology and Oncology, Johann Wolfgang Goethe University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany,

Purpose: Renal cell carcinoma (RCC) is the most common renal tumor and accounts for nearly 3 % of adult cancers. In the recent years, seven new targeted agents have been approved changing the treatment in metastatic RCC dramatically. So far, however, it remains unclear which sequence is best for those patients. This study analyzed retrospectively the outcome of patients treated with everolimus after failure of a vascular endothelial growth factor receptor-directed therapy and which therapies were used after everolimus.

Patients And Methods: In a retrospective analysis, patients receiving everolimus after failure of first-line VEGFR-directed therapy have been analyzed in regard to response, duration of treatment and subsequent therapies. In total, the data of 81 patients have been analyzed.

Results: The most observed first-line therapy was sunitinib followed by sorafenib. Thirty-two patients received everolimus as second-line therapy, and 49 as third-line therapy. The median duration of treatment with everolimus was 4.5 months. Seventy-seven of eighty-one patients (95 %) received a further therapy after discontinuation of everolimus. The agents administered beyond were sunitinib (28.6 %), sorafenib (28.6 %) and 42.8 % received other therapies. Twenty-seven patients received an additional sequence of therapy (fourth to fifth line). Fifty-eight percentage of patients have still been alive at time of analysis.

Conclusion: The duration of everolimus therapy beyond failure of anti-VEGF-directed therapy and the reported time to progression was in the range of the RECORD-1 trial in daily practice as well. After failure of everolimus, reexposure to tyrosine kinase inhibitors is a common clinical practice and demonstrates a clinical benefit of therapies beyond everolimus.
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http://dx.doi.org/10.1007/s00432-014-1610-xDOI Listing
May 2014

Temsirolimus for advanced renal cell carcinoma.

Expert Rev Anticancer Ther 2014 Jan 6;14(1):9-21. Epub 2013 Dec 6.

Medizinische Klinik II, J.W. Goethe Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt, Germany.

Renal cell carcinomas (RCCs) represent one of the ten leading cancer entities with an increasing incidence especially in the western world. Unfortunately, about 25% of the patients develop metastatic RCC (mRCC) associated with a most unfavorable prognosis. In the recent years, various new agents targeting VEGF or VEGF receptor (VEGFR) or the mTOR pathway have been approved for the treatment of mRCC with significant prolongation of progression-free survival and, in part, of overall survival (OS). Targeting the mTOR kinase is an interesting option for mRCC. Temsirolimus, one of the available mTOR inhibitors, has been approved as a single agent in poor-risk mRCC patients based on the pivotal Phase III trial showing a significant superiority in OS versus IFN-α or temsirolimus + IFN-α, which has been verified by a pivotal Phase III trial. The benefit has been shown for clear cell carcinoma and papillary RCC as well. For poor prognosis patients, temsirolimus improves median survival by 3.6 months. In second-line treatment compared with sorafenib following first-line treatment with sunitinib temsirolimus showed a relative progression-free survival benefit for patients with nonclear cell RCC with temsirolimus. The median OS for the temsirolimus group was 12.27 and 16.64 months for the sorafenib group. In 2007, the US FDA granted approval for temsirolimus for the treatment of advanced RCC.
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http://dx.doi.org/10.1586/14737140.2014.864562DOI Listing
January 2014

Temsirolimus in daily use: results of a prospective multicentre noninterventional study of patients with metastatic kidney cancer.

Eur Urol 2014 Aug 31;66(2):275-81. Epub 2013 Aug 31.

Department of Urology, Helios Hospital, Erfurt, Germany.

Background: Temsirolimus (TEMSR) was approved for treating advanced renal cell carcinoma (RCC) in 2007. Based on the data from a single phase 3 trial, it is recommended explicitly as first-line therapy for patients with a poor clinical prognosis.

Objective: The aim of this prospective multicentre trial (STARTOR) was to examine the effectiveness of TEMSR in daily clinical practice with a broader indication in the treatment of metastatic RCC.

Design, Setting, And Participants: Metastatic RCC patients treated with 25mg of TEMSR weekly were submitted to a prospective systematic evaluation and follow-up in 87 German centres between January 2008 and October 2011 using standardised procedures.

Outcome Measurements And Statistical Analysis: All data were centrally analysed by an independent clinical research organisation.

Results And Limitations: This interim analysis of the STARTOR study included 386 patients. The observed toxicity was tolerable, the median dose intensity was 91% (interquartile range: 79-100%), and the median treatment duration was 20.1 wk (95% confidence interval [CI], 17.0-23.3 wk). Clinical benefit was seen in 157 patients (40.7%); the median progression-free and overall survival were 4.9 mo (95% CI, 4.2-5.6) and 11.6 mo (95% CI, 9.3-13.9), respectively. The effectiveness of TEMSR did not differ significantly in relation to the patient's age, histologic RCC subtype, or line of treatment. The major limitations were the noninterventional study design, limited information about Memorial Sloan-Kettering Cancer Center risk factors and detailed toxicity, and the lack of central radiologic review.

Conclusions: TEMSR is an effective and largely well-tolerated treatment alternative for metastatic RCC patients in daily clinical practice, irrespective of the patient's age, histologic RCC subtype, or line of treatment.
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http://dx.doi.org/10.1016/j.eururo.2013.08.055DOI Listing
August 2014

Everolimus in metastatic renal cell carcinoma after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy: results of an interim analysis of a non-interventional study.

Onkologie 2013 25;36(3):95-100. Epub 2013 Feb 25.

University Hospital Frankfurt, Medical Clinic II, Frankfurt/Main, Germany.

Background: Everolimus is approved for treatment of anti-vascular endothelial growth factor (VEGF)-refractory patients with metastatic renal cell carcinoma (mRCC). Clinical trials rarely mirror treatment reality. Thus, a broader evaluation of everolimus is valuable for routine use.

Patients And Methods: A German multicenter non-interventional study documented mRCC patients starting everolimus after failure of initial VEGF-targeted therapy. Primary endpoint was effectiveness, defined as time to progression (TTP) according to investigator assessment (time from first dose to progression).

Results: Of 382 documented patients, 196 were included in this interim analysis. In the efficacy population (n = 165), median TTP was 7.0 months (95% confidence interval (CI) 5.1-9.0). Among patients with < or ≥ 6 months of previous VEGF-targeted therapy, median TTP was 6.6 months (95% CI 3.8-not estimable) and 7.4 months (95% CI 4.6-9.6), respectively. Most common adverse events were anemia (13%) and dyspnea (14%). Physicians assessed high tolerance and documented high adherence to everolimus therapy (approximately 97%).

Conclusion: In routine clinical practice, everolimus is effective, as measured by median TTP (longer than median progression-free survival in RECORD-1 trial), and well tolerated. Our results support everolimus use in anti-VEGF-refractory patients with mRCC.
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http://dx.doi.org/10.1159/000348522DOI Listing
September 2013

GLUT1 expression patterns in different Hodgkin lymphoma subtypes and progressively transformed germinal centers.

BMC Cancer 2012 Dec 10;12:586. Epub 2012 Dec 10.

Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany.

Background: Increased glycolytic activity is a hallmark of cancer, allowing staging and restaging with 18F-fluorodeoxyglucose-positron-emission-tomography (PET). Since interim-PET is an important prognostic tool in Hodgkin lymphoma (HL), the aim of this study was to investigate the expression of proteins involved in the regulation of glucose metabolism in the different HL subtypes and their impact on clinical outcome.

Methods: Lymph node biopsies from 54 HL cases and reactive lymphoid tissue were stained for glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA) and lactate exporter proteins MCT1 and MCT4. In a second series, samples from additional 153 HL cases with available clinical data were stained for GLUT1 and LDHA.

Results: Membrane bound GLUT1 expression was frequently observed in the tumor cells of HL (49% of all cases) but showed a broad variety between the different Hodgkin lymphoma subtypes: Nodular sclerosing HL subtype displayed a membrane bound GLUT1 expression in the Hodgkin-and Reed-Sternberg cells in 56% of the cases. However, membrane bound GLUT1 expression was more rarely observed in tumor cells of lymphocyte rich classical HL subtype (30%) or nodular lymphocyte predominant HL subtype (15%). Interestingly, in both of these lymphocyte rich HL subtypes as well as in progressively transformed germinal centers, reactive B cells displayed strong expression of GLUT1. LDHA, acting downstream of glycolysis, was also expressed in 44% of all cases. We evaluated the prognostic value of different GLUT1 and LDHA expression patterns; however, no significant differences in progression free or overall survival were found between patients exhibiting different GLUT1 or LDHA expression patterns. There was no correlation between GLUT1 expression in HRS cells and PET standard uptake values.

Conclusions: In a large number of cases, HRS cells in classical HL express high levels of GLUT1 and LDHA indicating glycolytic activity in the tumor cells. Although interim-PET is an important prognostic tool, a predictive value of GLUT1 or LDHA staining of the primary diagnostic biopsy could not be demonstrated. However, we observed GLUT1 expression in progressively transformed germinal centers and hyperplastic follicles, explaining false positive results in PET. Therefore, PET findings suggestive of HL relapse should always be confirmed by histology.
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http://dx.doi.org/10.1186/1471-2407-12-586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537691PMC
December 2012

The dual PI3K/mTOR inhibitor NVP-BGT226 induces cell cycle arrest and regulates Survivin gene expression in human pancreatic cancer cell lines.

Tumour Biol 2012 Jun 15;33(3):757-65. Epub 2011 Dec 15.

Medical Clinic II, Hematology/Oncology, University Hospital, JW Goethe University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany.

The phosphatidylinositol-3-kinase (PI3K) pathway is one of the most commonly activated signaling pathways in pancreatic cancer and is a target of interest for new therapeutic approaches. NVP-BGT226 is a novel dual class PI3K/mammalian target of rapamycin (mTOR) inhibitor that has entered Phase I/II clinical trials. We analyzed the effect of NVP-BGT226 (10-100 nM) on the pancreatic cell lines Panc-1, BxPc-3, AsPC-1 and MiaPaCa-2 in regard to cell viability, induction of apoptosis, cell cycle, and expression of the antiapoptotic genes Survivin, MCL-1, BCL-2 and BCL-xL. Cell viability decreased within 24-72 h after exposure to about 50% compared to untreated control cells in a concentration- but not time-dependent manner. Cell cycle analysis revealed that NVP-BGT226 induced predominantly G0/G1 cell cycle arrest. Additionally, real-time RT-PCR and Western blot analysis showed a remarkable decrease of Survivin expression. Originally designed as a dual inhibitor, there was only a significant inhibition of p-mTOR. In summary, the dual PI3K/mTOR inhibitor NVP-BGT226 induces G0/G1 arrest and acts, at least, partially via downregulation of Survivin.
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http://dx.doi.org/10.1007/s13277-011-0290-2DOI Listing
June 2012

Defining the critical hurdles in cancer immunotherapy.

J Transl Med 2011 Dec 14;9:214. Epub 2011 Dec 14.

Earle A, Chiles Research Institute, Robert W, Franz Research Center, Providence Cancer Center, Providence Portland Medical Center, Portland, OR, USA.

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer.
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http://dx.doi.org/10.1186/1479-5876-9-214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338100PMC
December 2011

Clinical efficacy of immunochemotherapy with fludarabine, epirubicin and rituximab in the treatment for chronic lymphocytic leukaemia and prolymphocytic leukaemia.

Eur J Haematol 2011 Nov 23;87(5):426-33. Epub 2011 Aug 23.

Hematology and Oncology, Frankfurt Medical Clinic II, Johann-Wolfgang-Goethe University Hospital, Theodor-Stern-Kai 7, Frankfurt, Germany.

Despite some considerable progress in the therapy for chronic lymphocytic leukaemia (CLL) owing to fludarabine-based regimens and rituximab, no curative treatment is available so far. We conducted an explorative phase II study in patients with CLL, prolymphocytic leukaemia (PLL) and leukaemic lymphoplasmacytic lymphoma (LL) with the combination of fludarabine, epirubicin and rituximab (FER) to improve the complete remission (CR) rate and progression-free survival (PFS). Fludarabine 25 mg/m(2) was administered i.v. on days 1-5 and epirubicin 25 mg/m(2) i.v. on days 4 and 5, and rituximab was added at a dose of 375 mg/m(2) i.v. day 1 in the first cycle and at a dose of 500 mg/m(2) in all consecutive cycles. Patients exhibiting responsive disease after FER were eligible to receive maintenance therapy of up to 12 cycles of rituximab 375 mg/m(2) bimonthly. Forty-four patients (38 CLL, 4 PLL and 2 LL) with a median age of 65 yrs (43-84 yrs) were evaluable. Seventeen patients with CLL had stage Binet C, 14 Binet B and seven symptomatic or rapid progressive stage Binet A. Cytogenetic features showed normal karyotype in nine cases, an isolated deletion (del) 13q in 12 patients, trisomy 12 in 7, del 11 in two and del 17p in 4. Half of the patients (48%) had mutated IgVH genes. Treatment with FER achieved an overall response rate of 95%, including 63% CRs and 32% PRs. Haematological toxicity was considerable. After a median follow-up period of 34 months (range: 8-84 months), median PFS was 61 months and overall survival was yet not reached. All patients with PLL and LL achieved CR. The data support the high efficacy of the combination of rituximab with chemotherapy (FE) and are suggestive of possible benefit with rituximab maintenance therapy for PFS and DFS.
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http://dx.doi.org/10.1111/j.1600-0609.2011.01680.xDOI Listing
November 2011

Results of a phase II trial of S-1 as first-line treatment of metastatic pancreatic cancer (CESAR-study group).

Invest New Drugs 2012 Jun 12;30(3):1184-92. Epub 2011 Apr 12.

Department of Haematology and Medical Oncology, University of Bochum (Marienhospital Herne), Herne, Germany.

Purpose: S-1, an oral fluoropyrimidine derivative, has previously demonstrated anticancer efficacy in pancreatic cancer (PC), predominantly in Asian populations. This study evaluated the antitumor effect and safety of S-1 in Caucasian patients with metastatic PC.

Methods: Chemotherapy-naïve patients received S-1 orally at 30 mg/m(2) twice daily (BID) for 2 weeks, repeated every 3 weeks. Primary endpoint was ORR. Secondary endpoints included PFS, OS and safety assessment. The trial had a Simon's two-stage design with 22 patients evaluable for efficacy in stage 1 and an additional 18 patients in stage 2, if ≥3/22 patients had a confirmed response at the first stage.

Results: Three out of 27 patients showed PR, however, detection of asymptomatic brain metastases in one of them prevented this study from proceeding to stage 2. The median PFS and OS for all patients was 3.5 and 9.1 months, respectively. The median duration of disease control for patients with SD or PR (n = 17) was 4.3 months. S-1 was well tolerated; fatigue was the most frequent grade 3/4 adverse event.

Conclusions: Efficacy data of PFS and OS are at least comparable to gemcitabine, the current standard of care. S-1 is active in Caucasian patients with metastatic PC.
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http://dx.doi.org/10.1007/s10637-011-9665-xDOI Listing
June 2012

The preclinical and clinical activity of aviscumine: a potential anticancer drug.

Eur J Cancer 2011 Jul 12;47(10):1450-7. Epub 2011 Apr 12.

Universitätsklinik Innsbruck, Department of Internal Medicine, Anichstrasse 35, A-6020 Innsbruck, Austria.

Extracts from the European mistletoe plant Viscumalbum have been studied for decades for their direct and indirect anticancer activity. Therefore, scientists were interested in identifying the active compound (mistletoe lectin) in these extracts and making it available as a highly purified molecule for drug development. Recombinant mistletoe lectin (INN: aviscumine) was produced in Escherichiacoli. It has been shown to have immunomodulatory and cytotoxic activity in invitro and in animal models and can target tumour cells. Clinical phase I studies also demonstrated immunomodulatory activity, which appears to have a positive effect on disease stabilisation. This review explores the current knowledge base for aviscumine's mechanism of action, efficacy and side-effects in both preclinical studies and clinical trials, and it considers aviscumine's potential as a cancer therapy.
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http://dx.doi.org/10.1016/j.ejca.2011.02.022DOI Listing
July 2011

Downregulation of STAT3 signaling induces apoptosis but also promotes anti-apoptotic gene expression in human pancreatic cancer cell lines.

Tumour Biol 2011 Jun 21;32(3):493-500. Epub 2010 Dec 21.

Department of Internal Medicine II, Hematology and Oncology, University Hospital, Johann Wolfgang Goethe University, Frankfurt, Germany.

Signal transducer and activator of transcription 3 (STAT3) is a key regulator of cytokine signaling pathways that regulates gene expression. In pancreatic cancer, constitutive activation of STAT3 contributes to oncogenesis by preventing apoptosis through upregulation of anti-apoptotic proteins. We have examined the inhibition of STAT3 as a potential therapeutic approach in pancreatic cancer. siRNA targeting STAT3 was used to evaluate the role of STAT3 in modulating the expression of Survivin/BIRC5 and BCL-xL in the pancreatic cancer cell lines PANC-1 and BxPC-3 and induction of apoptosis. Expression of STAT3, Survivin/BIRC5, and BCL-xL on mRNA and protein level was measured by real-time RT-PCR and Western blot analysis 24, 48, and 72 h after transfection. STAT3 downregulation resulted in a decrease of cell viability in both cell lines and induced apoptosis in BxPC-3 cells. Despite significant inhibition of STAT3, the expression of the anti-apoptotic genes Survivin/BIRC5 and BCL-xL were not subsequently downregulated. Even more, the cell line BxPC-3 shows a significant increase of Survivin/BIRC5 and BCL-xL mRNA after 48-72 h as a result of STAT3 downregulation. Inactivation of STAT3 in pancreatic cancer cell lines induces apoptosis but also may promote the expression of anti-apoptotic genes.
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http://dx.doi.org/10.1007/s13277-010-0143-4DOI Listing
June 2011

[Outlook: Future therapy of renal cell carcinoma].

Onkologie 2010 22;33 Suppl 1:18-20. Epub 2010 Jan 22.

Medizinische Klinik II, Hämatologie/Onkologie, J.W. Goethe-Universität, Frankfurt/M.

Targeted therapies have fundamentally altered the therapy of metastatic renal cell carcinoma (mRCC). Sunitinib today is an internationally recommended reference standard in first-line therapy; other drugs such as Temsirolimus, Everolimus, Bevacizumab (in combination with Interferon-alpha) and Sorafenib are part of the therapeutic arsenal. Practitioners thus have now more and better therapeutic options at hand, leading to a significantly improved prognosis for mRCC patients. Numerous ongoing research activities aim at the improvement of the benefits of the new compounds in the metastatic situation or application earlier in the course of the disease. Key aspects of future development in RCC are the optimization of the current therapy options by developing new targeted therapies, the search for the best combinations and sequences including the role of nephrectomy and the assessment in the adjuvant or neo-adjuvant setting. The following contribution provides an overview of ongoing studies, thus giving insight into the future therapy of RCC.
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http://dx.doi.org/10.1159/000265684DOI Listing
June 2010